Finding genes for childhood obesity

Researchers have identified four genes newly associated with severe childhood obesity. They also found an increased
burden of rare structural variations in severely obese children.

The team found that structural variations can delete sections of DNA that help to maintain protein receptors known to
be involved in the regulation of weight. These receptors are promising targets for the development of new drugs against
obesity.

As one of the major health issues affecting modern societies, obesity has increasingly received public attention.
Genes, behaviour and environment, all contribute to the development of obesity.

Children with severe obesity are more likely to have a strong genetic contribution. This study has enhanced
understanding of how both common and rare variants around specific genes and genetic regions are involved in severe
childhood obesity.

"We've known for a long time that changes to our genes can increase our risk of obesity. For
example, the gene FTO has been unequivocally associated with BMI, obesity and other obesity-related traits,"
says Dr Eleanor Wheeler, first author from the Wellcome Trust Sanger Institute. "In our study of
severely obese children, we found that variations in or near two of the newly associated genes seem to have a
comparable or greater effect on obesity than the FTO gene: PRKCH and RMST."

" Our study adds evidence that a range of both rare and common genetic variants are responsible for severe
childhood obesity. "

Dr Inês Barroso

The team found that different genes can be involved in severe childhood obesity compared to obesity in adults.

Rare genetic changes in one of the newly associated genes, LEPR, are known to cause a severe form of early onset
obesity. The team identified a more common variant in this gene, found in 6 per cent of the population, that can
increase a person’s risk of obesity. This finding is an example of where rare and more common variations around
the same gene or region can influence the risk of severe obesity.

Some of the children in this study had an increased number of structural variations of their DNA that delete G-protein
coupled receptors, important receptors in the regulation of weight. These receptors are key targets for current drug
development and may have potential therapeutic implications for obesity.

"Some children will be obese because they have severe mutations, but our research indicates that
some may have a combination of severe mutations and milder acting variants that in combination contribute to their
obesity," says Professor Sadaf Farooqi, co-lead author from the University of Cambridge. "As
we uncover more and more variants and genetic links, we will gain a better basic understanding of obesity, which in
turn will open doors to areas of clinically relevant research."

As part of the UK10K project the team are now exploring all the genes of 1000
children with severe obesity in whom a diagnostic mutation has not been found. This work will find new severe mutations
that may explain the causes of obesity in other children.

"Our study adds evidence that a range of both rare and common genetic variants are responsible for
severe childhood obesity," says Dr Inês Barroso, co-lead author from the Wellcome Trust Sanger Institute.
"This work brings us a step closer to understanding the biology underlying this severe form of
childhood obesity and providing a potential diagnosis to the children and their parents."

University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and
research at the highest international levels of excellence. It admits the very best and brightest students, regardless
of background, and offers one of the UK's most generous bursary schemes. The University of Cambridge's reputation for
excellence is known internationally and reflects the scholastic achievements of its academics and students, as well as
the world-class original research carried out by its staff. Some of the most significant scientific breakthroughs
occurred at the University, including the splitting of the atom, invention of the jet engine and the discoveries of
stem cells, plate tectonics, pulsars and the structure of DNA. From Isaac Newton to Stephen Hawking, the University has
nurtured some of history's greatest minds and has produced more Nobel Prize winners than any other UK institution with
over 80 laureates.

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Institute of Metabolic Science

The Institute of Metabolic Science is a joint venture between the University of Cambridge, the Medical Research Council
and Cambridge University Hospitals NHS Foundation Trust. The Institute of Metabolic Science is unique in the UK, being
focussed on understanding the biological basis of diabetes, obesity and metabolic disorders, all of which are major and
increasing threats to public health, and on translating these scientific discoveries into improved patient care and
disease prevention.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

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The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.